Cenderitide

Cenderitide (also known as chimeric natriuretic peptide or CD-NP) is a natriuretic peptide developed by the Mayo Clinic as a potential treatment for heart failure.[1][2][3] Cenderitide is created by the fusion of the 15 amino acid C-terminus of the snake venom dendroaspis natriuretic peptide (DNP) with the full C-type natriuretic peptide (CNP) structure[2]. This peptide chimera is a dual activator of the natriuretic peptide receptors NPR-A and NPR-B and therefore exhibits the natriuretic and diuretic properties of DNP, as well as the antiproliferative and antifibrotic properties of CNP.[1][3]

Cenderitide
Legal status
Legal status
  • Investigational
Identifiers
  • glycyl-L-leucyl-L-seryl-L-lysylglycyl-L-cysteinyl-L-phenylalanylglycyl-L-leucyl-L-lysyl-L-leucyl-L-α-aspartyl-L-arginyl-L-isoleucylglycyl-L-seryl-L-methionyl-L-serylglycyl-L-leucylglycyl-L-cysteinyl-L-prolyl-L-seryl-L-leucyl-L-arginyl-L-α-aspartyl-L-prolyl-L-arginyl-L-prolyl-L-asparaginyl-L-alanyl-L-prolyl-L-seryl-L-threonyl-L-seryl-L-alanine, cyclic (6→22)-disulfide
CAS Number
DrugBank
UNII

Molecular problem: fibrosis

When faced with pressure overload, the heart attempts to compensate with a number of structural alterations including hypertrophy of cardiomyocytes and increase of extracellular matrix (ECM) proteins.[4][5] Rapid accumulation of ECM proteins causes excessive fibrosis resulting in decreased myocardial compliance and increased myocardial stiffness.[5][6] The exact mechanisms involved in excessive fibrosis are not fully understood but there is evidence that supports involvement from local growth factors FGF-2, TGF-beta and platelet-derived growth factor.[7][8][9] TGF-β1 plays an important role in cardiac remodelling through the stimulation of fibroblast proliferation, ECM deposition and myocyte hypertrophy.[10][11][12] The increase in TGF-beta 1 expression in a pressure-overloaded heart correlates with the degree of fibrosis, suggesting TGF-beta 1 involvement in the progression from a compensated hypertrophy to failure.[13][14] Through an autocrine mechanism, TGF-beta 1 acts on fibroblasts by binding TGF-beta 1 receptors 1 and 2. Upon receptor activation, the receptor-associated transcription factor Smad becomes phosphorylated and associates with Co-Smad.[15] This newly formed Smad-Co-Smad complex enters the nucleus where it acts as a transcription factor modulating gene expression.[15] Cardiac remodelling of the ECM is also regulated by the CNP/NPR-B pathway as demonstrated by the improved outcomes in transgenic mice with CNP over-expression subjected to myocardial infarction.[16][17] Binding of CNP to NPR-B catalyzes the synthesis of cGMP, which is responsible for mediating the anti-fibrotic effects of CNP.[18] Fibrotic heart tissue is associated with an increase risk of ventricular dysfunction which can ultimately lead to heart failure.[5][19] Thus, anti-fibrotic strategies are a promising approach in the prevention and treatment of heart failure.

Molecular mechanism

As cenderitide interacts with both NRP-A and NRP-B, this drug has antifibrotic potential.[1] Binding of cenderitide to NRP-B elicits an antifibrotic response by catalyzing formation of cGMP similar to the response seen with endogenous CNP. Additionally, in vitro study of human fibroblasts demonstrates that cenderitide reduces TGF-beta 1 induced collagen production.[1][20] These two proposed mechanisms illustrate therapeutic potential for the reduction of fibrotic remodelling in the hypertensive heart. Through combined effects of CNP and DNP, cenderitide treatment results in a reduction in stress on the heart (through natriuresis/diuresis) and inhibition of pro-fibrotic, remodeling pathways.[1]

References
  1. McKie PM, Sangaralingham SJ, Burnett JC (September 2010). "CD-NP: an innovative designer natriuretic peptide activator of particulate guanylyl cyclase receptors for cardiorenal disease". Current Heart Failure Reports. 7 (3): 93–9. doi:10.1007/s11897-010-0016-6. PMID 20582736. S2CID 23726451.
  2. Lisy O, Huntley BK, McCormick DJ, Kurlansky PA, Burnett JC (July 2008). "Design, synthesis, and actions of a novel chimeric natriuretic peptide: CD-NP". Journal of the American College of Cardiology. 52 (1): 60–8. doi:10.1016/j.jacc.2008.02.077. PMC 2575424. PMID 18582636.
  3. Dickey DM, Burnett JC, Potter LR (December 2008). "Novel bifunctional natriuretic peptides as potential therapeutics". The Journal of Biological Chemistry. 283 (50): 35003–9. doi:10.1074/jbc.M804538200. PMC 3259864. PMID 18940797.
  4. Bonnin CM, Sparrow MP, Taylor RR (November 1981). "Collagen synthesis and content in right ventricular hypertrophy in the dog". The American Journal of Physiology. 241 (5): H708–13. doi:10.1152/ajpheart.1981.241.5.H708. PMID 7304760.
  5. Averill DB, Ferrario CM, Tarazi RC, Sen S, Bajbus R (April 1976). "Cardiac performance in rats with renal hypertension". Circulation Research. 38 (4): 280–8. doi:10.1161/01.res.38.4.280. PMID 131007.
  6. Weber KT (June 1989). "Cardiac interstitium in health and disease: the fibrillar collagen network". Journal of the American College of Cardiology. 13 (7): 1637–52. doi:10.1016/0735-1097(89)90360-4. PMID 2656824.
  7. Creemers EE, Pinto YM (February 2011). "Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart". Cardiovascular Research. 89 (2): 265–72. doi:10.1093/cvr/cvq308. PMID 20880837.
  8. Weber KT, Swamynathan SK, Guntaka RV, Sun Y (1999). "Angiotensin II and extracellular matrix homeostasis". The International Journal of Biochemistry & Cell Biology. 31 (3–4): 395–403. doi:10.1016/s1357-2725(98)00125-3. PMID 10224666.
  9. Swaney JS, Roth DM, Olson ER, Naugle JE, Meszaros JG, Insel PA (January 2005). "Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase". Proceedings of the National Academy of Sciences of the United States of America. 102 (2): 437–42. Bibcode:2005PNAS..102..437S. doi:10.1073/pnas.0408704102. PMC 544320. PMID 15625103.
  10. Villarreal FJ, Lee AA, Dillmann WH, Giordano FJ (April 1996). "Adenovirus-mediated overexpression of human transforming growth factor-beta 1 in rat cardiac fibroblasts, myocytes and smooth muscle cells". Journal of Molecular and Cellular Cardiology. 28 (4): 735–42. doi:10.1006/jmcc.1996.0068. PMID 8732501.
  11. Eghbali M, Tomek R, Sukhatme VP, Woods C, Bhambi B (August 1991). "Differential effects of transforming growth factor-beta 1 and phorbol myristate acetate on cardiac fibroblasts. Regulation of fibrillar collagen mRNAs and expression of early transcription factors". Circulation Research. 69 (2): 483–90. doi:10.1161/01.res.69.2.483. PMID 1860186.
  12. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (May 2002). "Myofibroblasts and mechano-regulation of connective tissue remodelling". Nature Reviews. Molecular Cell Biology. 3 (5): 349–63. doi:10.1038/nrm809. PMID 11988769. S2CID 3353563.
  13. Boluyt MO, O'Neill L, Meredith AL, Bing OH, Brooks WW, Conrad CH, Crow MT, Lakatta EG (July 1994). "Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Marked upregulation of genes encoding extracellular matrix components". Circulation Research. 75 (1): 23–32. doi:10.1161/01.res.75.1.23. PMID 8013079.
  14. Hein S, Arnon E, Kostin S, Schönburg M, Elsässer A, Polyakova V, Bauer EP, Klövekorn WP, Schaper J (February 2003). "Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms". Circulation. 107 (7): 984–91. doi:10.1161/01.cir.0000051865.66123.b7. PMID 12600911.
  15. Chen YG, Hata A, Lo RS, Wotton D, Shi Y, Pavletich N, Massagué J (July 1998). "Determinants of specificity in TGF-beta signal transduction". Genes & Development. 12 (14): 2144–52. doi:10.1101/gad.12.14.2144. PMC 317013. PMID 9679059.
  16. Wang Y, de Waard MC, Sterner-Kock A, Stepan H, Schultheiss HP, Duncker DJ, Walther T (2007). "Cardiomyocyte-restricted over-expression of C-type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice". European Journal of Heart Failure. 9 (6–7): 548–57. doi:10.1016/j.ejheart.2007.02.006. PMID 17407830.
  17. Langenickel TH, Buttgereit J, Pagel-Langenickel I, Lindner M, Monti J, Beuerlein K, Al-Saadi N, Plehm R, Popova E, Tank J, Dietz R, Willenbrock R, Bader M (March 2006). "Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B". Proceedings of the National Academy of Sciences of the United States of America. 103 (12): 4735–40. Bibcode:2006PNAS..103.4735L. doi:10.1073/pnas.0510019103. PMC 1450239. PMID 16537417.
  18. Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM (2009). "Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications". CGMP: Generators, Effectors and Therapeutic Implications. Handbook of Experimental Pharmacology. Vol. 191. pp. 341–66. doi:10.1007/978-3-540-68964-5_15. ISBN 978-3-540-68960-7. PMC 4855512. PMID 19089336.
  19. Kenchaiah S, Pfeffer MA (January 2004). "Cardiac remodeling in systemic hypertension". The Medical Clinics of North America. 88 (1): 115–30. doi:10.1016/s0025-7125(03)00168-8. PMID 14871054. S2CID 32530917.
  20. Ichiki T, Huntley BK, Sangaralingham SJ, Chen HH, Burnett Jr JC (2009). "A novel designer natriuretic peptide CD-NP suppresses TGF-beta 1 induced collagen type I production in human cardiac fibroblasts". Journal of Cardiac Failure. 15 (6 supplement): S34. doi:10.1016/j.cardfail.2009.06.318.
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